Bovine herpesvirus 1 (BHV-1), is the causative agent of infectious bovine rhinotracheitis (IBR), and is an economically significant viral pathogen of cattle that can cause severe respiratory infection, conjunctivitis, abortions, vulvovaginitis, balanoposthitis, and systemic infection in neonate calves (Wyler et al. (1989) HERPESVIRUS DISEASES OF CATTLE, HORSES, AND PIGS 1-72 (Boston) In G. Witman (ed.) Kluwer Academic Publishers). The nucleotide sequence of the BHV-1 genome (136 kb) is known. It generally contains 67 unique genes and 2 genes, both duplicated, in the inverted repeats. In general, the BHV-1 genes exhibit homology at the amino acid sequence level to those of other alphaherpesviruses (HSV-1, VZV, EHV-1) and are arranged in similar order BHV-1 is a member of the varicellovirus genus, part of the subfamily Alphaherpesvirinae (family Herpesviridae). The subfamily includes human herpesvirus 3, pseudorabies virus, and bovine and equid herpesviruses.
BHV-1 infection is also a component of the upper respiratory tract infection referred to as “shipping fever” or bovine respiratory complex (Tikoo et al. (1995) Adv. Virus Res. 45:191; US patent publication no. 2004-0185056). BHV-1 is not the sole infectious agent associated with shipping fever, but it initiates the disorder by immunosuppressing infected cattle, which generally results in secondary bacterial infections and pneumonia increased susceptibility to secondary infection correlates with depressed cell-mediated immunity after BHV-1 infection (Carter et al. (1989) J. Virol. 63:1525; Griebel et al. (1990) J. Gen. Virol. 71:369; Griebel et al. (1987) Viral Immunol. 1:287; Griebel et al. (1987) Viral Immunol. 1:267). BHV-1 generally establishes lifelong latency in ganglionic neurons of the peripheral nervous system after initial replication in mucosal epithelium and results in animals being contagious beyond acute infection. Reactivation from latency generally results in virus shedding and transmission to other susceptible animals. Reactivation generally occurs after natural or corticosteroid-induced stress (Rock et al. (1992) J. Virol. 66:2484; Sheffy and Davies (1972) Proc. Soc. Exp. Biol. Med. 140:974).
In an effort to control BHV-1 infections, conventional killed-virus and attenuated live-virus vaccines have been developed. Commercially available vaccines, attenuated live-virus vaccines for example, may cause immunosuppression or immune depression, or other alterations of the host immune system. These alterations can be attributed to BHV-1 encoded proteins that suppress or otherwise alter the infected host's immune system. This immunosupression may result in the inability of these vaccines to prevent establishment of a latent infection by a virulent field strain of BHV-1 (see, e.g., Gerber et al. (1978) Am. J. Vet. Res. 39:753: Jericho et al. (1983) Can J. Com. Med. 47:133; Pastoret et al. (1980) Infect. Immun. 29:483).
A trend in current vaccines is co-administered or combination vaccines, which generally contain antigens from multiple agents or organisms. These vaccines can provide vaccination and protection for multiple agents and/or diseases and may be given in a single time point or administration. In vaccines containing BHV-1, BHV-1 may affect or change the host immune response against co-administered. In one example, the immune response to antigens co-administered with BHV-1 or present in combination vaccines along with BHV-1 may be suppressed, decreased, or otherwise changed, relative to the host immune response to those antigens when administered without BHV-1. The affected or altered immune response may reduce the ability of vaccine antigens co-administered with BHV-1 to stimulate an immune response protective against infection and/or disease caused by the infectious agents from which the co-administered antigens were derived. Prior and current attenuated BHV-1 viruses do not generally address BHV-1 immunosuppression and/or altered host immune responses against co-administered antigens.